Protein Disulfide Oxidoreductases and Other Proteins with a Thioredoxin fold; The thioredoxin (TRX)-like superfamily is a large, diverse group of proteins containing a TRX fold. Many members contain a classic TRX domain with a redox active CXXC motif. They function as protein disulfide oxidoreductases (PDOs), altering the redox state of target proteins via the reversible oxidation of their active site dithiol. The PDO members of this superfamily include the families of TRX, protein disulfide isomerase (PDI), tlpA, glutaredoxin, NrdH redoxin, and bacterial Dsb proteins (DsbA, DsbC, DsbG, DsbE, DsbDgamma). Members of the superfamily that do not function as PDOs but contain a TRX-fold domain include phosducins, peroxiredoxins, glutathione (GSH) peroxidases, SCO proteins, GSH transferases (GST, N-terminal domain), arsenic reductases, TRX-like ferredoxins and calsequestrin, among others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676318072  58 VGDAIPAVEVFE--GEPGNKVNLAELFKGKKGVLFGVPGAFTPGCS---------------------------------- 101
Cdd:cd03013     1 VGDKLPNVTLFEyvPGPPNPVNLSELFKGKKVVIFGVPGAFTPTCSaqhlpgyvenadelkakgvdevicvsvndpfvmk 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1676318072 102 ----------KVRLLADPTGAFGKETDLLLDDSLvsIFGNRRLKRFSMVVQDGIVKALNVEPDGTGLTCSLAPNIIS 168
Cdd:cd03013    81 awgkalgakdKIRFLADGNGEFTKALGLTLDLSA--AGGGIRSKRYALIVDDGKVKYLFVEEDPGDVEVSSAENVLK 155

Peroxiredoxin (PRX) family, PRX5-like subfamily; members are similar to the human protein, PRX5, a homodimeric TRX peroxidase, widely expressed in tissues and found cellularly in mitochondria, peroxisomes and the cytosol. The cellular location of PRX5 suggests that it may have an important antioxidant role in organelles that are major sources of reactive oxygen species (ROS), as well as a role in the control of signal transduction. PRX5 has been shown to reduce hydrogen peroxide, alkyl hydroperoxides and peroxynitrite. As with all other PRXs, the N-terminal peroxidatic cysteine of PRX5 is oxidized into a sulfenic acid intermediate upon reaction with peroxides. Human PRX5 is able to resolve this intermediate by forming an intramolecular disulfide bond with its C-terminal cysteine (the resolving cysteine), which can then be reduced by TRX, just like an atypical 2-cys PRX. This resolving cysteine, however, is not conserved in other members of the subfamily. In such cases, it is assumed that the oxidized cysteine is directly resolved by an external small-molecule or protein reductant, typical of a 1-cys PRX. In the case of the H. influenza PRX5 hybrid, the resolving glutaredoxin domain is on the same protein chain as PRX. PRX5 homodimers show an A-type interface, similar to atypical 2-cys PRXs.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676318072  58 VGDAIPAVEVFE--GEPGNKVNLAELFKGKKGVLFGVPGAFTPGCS---------------------------------- 101
Cdd:cd03013     1 VGDKLPNVTLFEyvPGPPNPVNLSELFKGKKVVIFGVPGAFTPTCSaqhlpgyvenadelkakgvdevicvsvndpfvmk 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1676318072 102 ----------KVRLLADPTGAFGKETDLLLDDSLvsIFGNRRLKRFSMVVQDGIVKALNVEPDGTGLTCSLAPNIIS 168
Cdd:cd03013    81 awgkalgakdKIRFLADGNGEFTKALGLTLDLSA--AGGGIRSKRYALIVDDGKVKYLFVEEDPGDVEVSSAENVLK 155

Redoxin; This family of redoxins includes peroxiredoxin, thioredoxin and glutaredoxin proteins.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676318072  57 KVGDAIPAVEVFE-GEPGNKVNLAElFKGKKGVLFGVPGAFTPGCS---------------------------------- 101
Cdd:pfam08534   1 KAGDKAPDFTLPDaATDGNTVSLSD-FKGKKVVLNFWPGAFCPTCSaehpyleklnelykekgvdvvavnsdndaffvkr 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1676318072 102 -------KVRLLADPTGAFGKETDLLLDDSLVSifgNRRLKRFSMVVQDGIVKALNVEPDGT 156
Cdd:pfam08534  80 fwgkeglPFPFLSDGNAAFTKALGLPIEEDASA---GLRSPRYAVIDEDGKVVYLFVGPEPG 138

Peroxiredoxin (PRX) family, PRX5-like subfamily; members are similar to the human protein, PRX5, a homodimeric TRX peroxidase, widely expressed in tissues and found cellularly in mitochondria, peroxisomes and the cytosol. The cellular location of PRX5 suggests that it may have an important antioxidant role in organelles that are major sources of reactive oxygen species (ROS), as well as a role in the control of signal transduction. PRX5 has been shown to reduce hydrogen peroxide, alkyl hydroperoxides and peroxynitrite. As with all other PRXs, the N-terminal peroxidatic cysteine of PRX5 is oxidized into a sulfenic acid intermediate upon reaction with peroxides. Human PRX5 is able to resolve this intermediate by forming an intramolecular disulfide bond with its C-terminal cysteine (the resolving cysteine), which can then be reduced by TRX, just like an atypical 2-cys PRX. This resolving cysteine, however, is not conserved in other members of the subfamily. In such cases, it is assumed that the oxidized cysteine is directly resolved by an external small-molecule or protein reductant, typical of a 1-cys PRX. In the case of the H. influenza PRX5 hybrid, the resolving glutaredoxin domain is on the same protein chain as PRX. PRX5 homodimers show an A-type interface, similar to atypical 2-cys PRXs.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676318072  58 VGDAIPAVEVFE--GEPGNKVNLAELFKGKKGVLFGVPGAFTPGCS---------------------------------- 101
Cdd:cd03013     1 VGDKLPNVTLFEyvPGPPNPVNLSELFKGKKVVIFGVPGAFTPTCSaqhlpgyvenadelkakgvdevicvsvndpfvmk 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1676318072 102 ----------KVRLLADPTGAFGKETDLLLDDSLvsIFGNRRLKRFSMVVQDGIVKALNVEPDGTGLTCSLAPNIIS 168
Cdd:cd03013    81 awgkalgakdKIRFLADGNGEFTKALGLTLDLSA--AGGGIRSKRYALIVDDGKVKYLFVEEDPGDVEVSSAENVLK 155

Peroxiredoxin (PRX) family; composed of the different classes of PRXs including many proteins originally known as bacterioferritin comigratory proteins (BCP), based on their electrophoretic mobility before their function was identified. PRXs are thiol-specific antioxidant (TSA) proteins also known as TRX peroxidases and alkyl hydroperoxide reductase C22 (AhpC) proteins. They confer a protective antioxidant role in cells through their peroxidase activity in which hydrogen peroxide, peroxynitrate, and organic hydroperoxides are reduced and detoxified using reducing equivalents derived from either TRX, glutathione, trypanothione and AhpF. They are distinct from other peroxidases in that they have no cofactors such as metals or prosthetic groups. The first step of catalysis, common to all PRXs, is the nucleophilic attack by the catalytic cysteine (also known as the peroxidatic cysteine) on the peroxide leading to cleavage of the oxygen-oxygen bond and the formation of a cysteine sulfenic acid intermediate. The second step of the reaction, the resolution of the intermediate, distinguishes the different types of PRXs. The presence or absence of a second cysteine (the resolving cysteine) classifies PRXs as either belonging to the 2-cys or 1-cys type. The resolving cysteine of 2-cys PRXs is either on the same chain (atypical) or on the second chain (typical) of a functional homodimer. Structural and motif analysis of this growing family supports the need for a new classification system. The peroxidase activity of PRXs is regulated in vivo by irreversible cysteine over-oxidation into a sulfinic acid, phosphorylation and limited proteolysis.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676318072  62 IPAVEVFeGEPGNKVNLAElFKGKKGVLFGVPGAFTPGCS---------------------------------------- 101
Cdd:cd02971     2 APDFTLP-ATDGGEVSLSD-FKGKWVVLFFYPKDFTPVCTtelcafrdlaeefakggaevlgvsvdspfshkawaekegg 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1676318072 102 -KVRLLADPTGAFGKETDLLLDDSlvsiFGNRRLKRFSMVV-QDGIVKALNVEPDGTG 157
Cdd:cd02971    80 lNFPLLSDPDGEFAKAYGVLIEKS----AGGGLAARATFIIdPDGKIRYVEVEPLPTG 133

AhpC/TSA family; This family contains proteins related to alkyl hydroperoxide reductase (AhpC) and thiol specific antioxidant (TSA).

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                  ....*....|....*....|....*....|....*....|...
gi 1676318072  58 VGDAIPAVEVFEGEpGNKVNLAElFKGKKGVLFGVPGAFTPGC 100
Cdd:pfam00578   1 VGDKAPDFELPDGD-GGTVSLSD-YRGKWVVLFFYPADWTPVC 41

Peroxiredoxin (PRX) family, AhpE-like subfamily; composed of proteins similar to Mycobacterium tuberculosis AhpE. AhpE is described as a 1-cys PRX because of the absence of a resolving cysteine. The structure and sequence of AhpE, however, show greater similarity to 2-cys PRXs than 1-cys PRXs. PRXs are thiol-specific antioxidant (TSA) proteins that confer a protective role in cells through their peroxidase activity in which hydrogen peroxide, peroxynitrate, and organic hydroperoxides are reduced and detoxified using reducing equivalents derived from either thioredoxin, glutathione, trypanothione and AhpF. The first step of catalysis is the nucleophilic attack by the peroxidatic cysteine on the peroxide leading to the formation of a cysteine sulfenic acid intermediate. The absence of a resolving cysteine suggests that functional AhpE is regenerated by an external reductant. The solution behavior and crystal structure of AhpE show that it forms dimers and octamers.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1676318072  56 IKVGDAIPAVEVfEGEPGNKVNLAELFKGKKGVLFGVPGAFTPGCSK 102
Cdd:cd03018     1 LEVGDKAPDFEL-PDQNGQEVRLSEFRGRKPVVLVFFPLAFTPVCTK 46

Peroxiredoxin (PRX) family, Bacterioferritin comigratory protein (BCP) subfamily; composed of thioredoxin-dependent thiol peroxidases, widely expressed in pathogenic bacteria, that protect cells against toxicity from reactive oxygen species by reducing and detoxifying hydroperoxides. The protein was named BCP based on its electrophoretic mobility before its function was known. BCP shows substrate selectivity toward fatty acid hydroperoxides rather than hydrogen peroxide or alkyl hydroperoxides. BCP contains the peroxidatic cysteine but appears not to possess a resolving cysteine (some sequences, not all, contain a second cysteine but its role is still unknown). Unlike other PRXs, BCP exists as a monomer. The plant homolog of BCP is PRX Q, which is expressed only in leaves and is cellularly localized in the chloroplasts and the guard cells of stomata. Also included in this subfamily is the fungal nuclear protein, Dot5p (for disrupter of telomere silencing protein 5), which functions as an alkyl-hydroperoxide reductase during post-diauxic growth.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1676318072  60 DAIPAVEVfEGEPGNKVNLAElFKGKKGVLFGVPGAFTPGCSK 102
Cdd:cd03017     1 DKAPDFTL-PDQDGETVSLSD-LRGKPVVLYFYPKDDTPGCTK 41